Signal Transducers and Activators of Transcription (STATs) are a family of DNA binding proteins that reside in the cytoplasm until they are activated by tyrosine phosphorylation. This phosphorylation event is catalyzed by members of the Janus family of tyrosine kinases, including JAK3 (Ihle, J. N. Adv. Immunol. 60: 1-35, 1995; Witthuhn, B. A., et al., Leukemia and Lymphoma. 32: 289-297, 1999).
The dual role of STATs as signaling molecules and transcription factors is reflected in their structure. All STAT proteins contain a DNA binding domain, an SH2 domain, and a transactivation domain necessary for transcriptional induction. In unstimulated cells, latent forms of STATs are predominantly localized in the cytoplasm. Ligand binding induces STAT proteins to bind with their SH2 domains to the tyrosine phosphorylated motifs in the intracellular domains of various transmembrane cell surface receptors (Horvath, C. M. and Darnell, J. E., Curr. Opin. Cell. Biol. 9(2): 233-239., 1997; Levy, D. E., Cytokine Growth Factor Rev. 8(1): 81-90, 1997).
Once STATs are bound to receptors, the receptor-associated Janus kinases (JAKs) phosphorylate STATs on a single tyrosine residue located near the SH2 domain. Two STATs then dimerize through specific reciprocal SH2-phosphotyrosine interactions. The dimerized STAT proteins can also form complexes with other DNA-binding proteins. The STAT dimers/complexes next translocate to the nucleus and utilize their DNA binding domain to interact with DNA response elements in promoters of target genes (Demoulin, J. B., et al., Mol. Cell. Biol. 16: 4710-6, 1996). STATs then interact directly or indirectly, via their transactivation domain, with components of the RNA polymerase II complex to activate transcription of target genes. Different ligands employ specific JAK and STAT family members, thus utilization of this pathway mandates specificity in signaling cascades and contributes to a diverse array of cellular responses. Janus kinases, including JAK3, are abundantly expressed in primary leukemic cells from children with acute lymphoblastic leukemia (ALL), the most common form of childhood cancer, and recent studies have correlated STAT activation in ALL cells with signals regulating apoptosis (Demoulin, J. B., et al., Mol. Cell. Biol. 16: 4710-6, 1996; Jurlander, J., et al., Blood. 89: 4146-4152, 1997; Kaneko, S., Suzuki, et al., Clin. Exp. Immun. 109: 185-193, 1997; and Nakamura, N., et al., J. Biol. Chem. 271: 19483-8, 1996).
Thus, JAK-3 is an important enzyme that plays an essential role in the function of lymphocytes, macrophages, and mast cells. Compounds which inhibit JAK-3 would be expected to be useful for treating or preventing diseases or conditions wherein the function of lymphocytes, macrophages, or mast cells is implicated, such as, leukemia, lymphoma, transplant rejection (e.g. pancreas islet transplant rejection, bone marrow transplant applications (e.g. graft-versus-host disease), autoimmune diseases (e.g. diabetes), and inflammation (e.g. asthma, inflammation associated with sun burn, and skin cancer). A continuing need exists for compounds and methods that are useful for the treatment and/or prevention of such conditions and diseases.
The present invention provides JAK-3 inhibiting compounds that are nontoxic in the administered dosage range. The JAK-3 inhibitors of the invention are useful for treating leukemia and lymphoma. The compounds are also useful to prevent skin cancer, as well as to treat or prevent sunburn and UVB-induced skin inflammation. In addition, the compounds of the present invention prevent the immunosuppressive effects of UVB radiation, and are useful to treat or prevent autoimmune diseases, inflammation, and transplant rejection.
The present invention provides a therapeutic method for treating leukemia or lymphoma comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
The present invention also provides a therapeutic method for preventing or reducing UV B radiation-induced inflammatory response in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
The present invention also provides a therapeutic method for inhibiting the release of prostaglandin E2 in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
The present invention also provides a therapeutic method for preventing or reducing UVB-induced skin edema or vascular permeability changes in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
The present invention also provides a therapeutic method for preventing or reducing UV B radiation-induced damage to epithelial cells or mutation frequency in skin in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
The present invention also provides a therapeutic method for protecting a mammal from tumorigenic effects of UVB light comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.
Representative JAK-3 inhibitors of the invention have also been found to exhibit significant anti-proliferative activity against T-cells, and have been found to inhibit IL-2 dependent cell proliferation. Thus, the compounds can be used to treat or prevent transplant complications (e.g. rejection of a donor organ transplant by the host immune system), and complications associated with bone marrow transplantation such as graft versus host disease.
In addition, the compounds of the invention are effective in treating and preventing autoimmune diseases, such as insulin dependent diabetes. The compounds are also effective in treating airway inflammation (asthma).
Accordingly, the invention also provides a therapeutic method for treating (or preventing) leukemia, transplant rejection, graft-verses host disease, inflammation, asthma, autoimmune diseases including diabetes, and inflammation related cancer development in the skin, comprising administering to the mammal in need thereof an effective amount of a compound of formula I.
The invention also provides novel compounds of formula I disclosed herein as well as pharmaceutical compositions comprising compounds of formula I.
A specific JAK-3 inhibitor useful in the medicamants and methods of the invention is a compound of formula I: 
wherein:
X is HN, R11N, S, O, CH2, or R11CH;
R11 is hydrogen, (C1-C4)alkyl, or (C1-C4)alkanoyl;
R1-R8 are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, or halo; wherein two adjacent groups of R1-R5 together with the phenyl ring to which they are attached may optionally form a fused ring, for example forming a naphthyl or a tetrahydronaphthyl ring; and further wherein the ring formed by the two adjacent groups of R1-R5 may optionally be substituted by 1, 2, 3, or 4 hydroxy, mercapto, amino, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, or halo; and
R9 and R10 are each independently hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo, or (C1-C4)alkanoyl; or R9 and R10 together are methylenedioxy; or a pharmaceutically acceptable salt thereof. Peferably, at least one of R2 and R3 is hydroxy. More preferably, at least one of R2 and R3 is hydroxy, and one of R1 to R5 is halo.